{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:31:01Z","timestamp":1787027461381,"version":"build-2736575974"},"reference-count":59,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004377","name":"Hong Kong Polytechnic University","doi-asserted-by":"publisher","award":["P0036848"],"award-info":[{"award-number":["P0036848"]}],"id":[{"id":"10.13039\/501100004377","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Elevated branched\u2010chain amino acids (BCAAs; leucine, valine, isoleucine) are linked to type 2 diabetes (T2D) risk, characterised by defective insulin secretion in pancreatic \u03b2\u2010cell and peripheral insulin resistance. Causative interaction between BCAA metabolism and these two diabetic pathogenesis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using publicly available datasets from the European population, we conducted a meta\u2010analysis of genome\u2010wide association studies (GWAS), followed by multi\u2010trait analysis of GWAS (MTAG), to identify genetic loci associated with BCAAs and their catabolites. Two\u2010sample bidirectional Mendelian Randomisation (MR) examined putative causal associations of genetically determined BCAAs and their catabolites with 10 traits related to insulin and glucose metabolism. Sensitivity analyses evaluated robustness and specificity of observed associations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MTAG identified 57.14%, 59.09%, and 63.41% novel genetic loci for circulating leucine, valine and isoleucine, respectively. Genetically elevated valine had a significant association with increased insulin fold change during oral glucose challenge test (OGTT) (\u03b2 [95% CI]\u2009=\u20090.135 [0.045, 0.225]), False discovery rate adjusted\n                      <jats:italic>p<\/jats:italic>\n                      \u2010value (\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>FDR<\/jats:sub>\n                      \u2009=\u20090.022), and suggestive association with fasting glucose level (\u03b2 [95% CI]\u2009=\u20090.031 [0.004, 0.058], inverse\u2010variance weighted\n                      <jats:italic>p<\/jats:italic>\n                      \u2010value [\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>IVW<\/jats:sub>\n                      ]\u2009=\u20090.025). In the reverse direction, genetically determined homeostasis model assessment of \u03b2\u2010cell (HOMA\u2010B) exhibited significant inverse associations with BCAAs (Leucine: \u03b2 [95% CI]\u2009=\u2009\u22120.140 [\u22120.244, \u22120.036],\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>FDR<\/jats:sub>\n                      \u2009=\u20090.034; Valine: \u03b2 [95% CI]\u2009=\u2009\u22120.147 [\u22120.255, \u22120.040],\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>FDR<\/jats:sub>\n                      \u2009=\u20090.030; Isoleucine: \u03b2 [95% CI]\u2009=\u2009\u22120.149 [\u22120.248, \u22120.049],\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>FDR<\/jats:sub>\n                      \u2009=\u20090.020). Moreover, \u03b2\u2010hydroxyisovalerate, a leucine\u2010derived catabolite, was inversely related to 2\u2010h glucose level after OGTT (\u03b2 [95% CI]\u2009=\u2009\u22120.149 [\u22120.227, \u22120.071],\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>FDR<\/jats:sub>\n                      \u2009=\u20090.045). In the reverse direction, genetically predicted peak insulin response was suggestively associated with elevated isoleucine catabolite, 2\u2010hydroxy\u20103\u2010methylvalerate (\u03b2 [95% CI]\u2009=\u20090.074 [0.018, 0.130],\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>IVW<\/jats:sub>\n                      \u2009=\u20099.20\u2009\u00d7\u200910\n                      <jats:sup>\u22123<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our genetic analysis indicates BCAA catabolism and insulin secretion\/action interact with each other; their aberrance might form a vicious cycle promoting T2D progression.<\/jats:p>\n                  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